National Human Genome Center, Rui-Jin Hospital, Shanghai Jiaotong University School of Medicine, 351 Guo Shou-Jing Road, Shanghai, People's Republic of China.
J Clin Invest. 2010 Jan;120(1):223-41. doi: 10.1172/JCI38012. Epub 2009 Dec 14.
The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Here, in a human genome-wide survey, we identified scavenger receptor class A, member 5 (SCARA5) as a candidate tumor suppressor gene located on chromosome 8p. We found that SCARA5 expression was frequently downregulated as a result of promoter hypermethylation and allelic imbalance and was associated with vascular invasion in human hepatocellular carcinoma (HCC). Furthermore, SCARA5 knockdown via RNAi markedly enhanced HCC cell growth in vitro, colony formation in soft agar, and invasiveness, tumorigenicity, and lung metastasis in vivo. By contrast, SCARA5 overexpression suppressed these malignant behaviors. Interestingly, SCARA5 was found to physically associate with focal adhesion kinase (FAK) and inhibit the tyrosine phosphorylation cascade of the FAK-Src-Cas signaling pathway. Conversely, silencing SCARA5 stimulated the signaling pathway via increased phosphorylation of certain tyrosine residues of FAK, Src, and p130Cas; it was also associated with activation of MMP9, a tumor metastasis-associated enzyme. Taken together, these data suggest that the plasma membrane protein SCARA5 can contribute to HCC tumorigenesis and metastasis via activation of the FAK signaling pathway.
表观遗传抑制肿瘤抑制基因是癌发生和转移过程中的一个关键事件。在这里，在一个人类全基因组调查中，我们确定了清道夫受体 A 成员 5（SCARA5）作为位于 8p 染色体上的候选肿瘤抑制基因。我们发现，由于启动子过度甲基化和等位基因失衡，SCARA5 的表达经常下调，并且与人类肝细胞癌（HCC）中的血管侵犯有关。此外，通过 RNAi 敲低 SCARA5 可显著增强 HCC 细胞在体外的生长、软琼脂中的集落形成以及体内的侵袭性、致瘤性和肺转移。相比之下，SCARA5 的过表达抑制了这些恶性行为。有趣的是，发现 SCARA5 与粘着斑激酶（FAK）物理结合，并抑制 FAK-Src-Cas 信号通路的酪氨酸磷酸化级联反应。相反，沉默 SCARA5 通过增加 FAK、Src 和 p130Cas 的某些酪氨酸残基的磷酸化来刺激信号通路；它还与肿瘤转移相关酶 MMP9 的激活有关。总之，这些数据表明，质膜蛋白 SCARA5 可以通过激活 FAK 信号通路促进 HCC 的发生和转移。
